This Phase I proposal is to develop glycopeptide neoglycosides against VanA-resistant and VanB-resistant organisms. The clinical relevance of such compounds stems from the sharp rise in VRE (vancomycin-resistant enterococci, and more recently staphylococci) infections from below 0.5% in 1989 to >30% in 2000 in the U.S. alone. This rise in vancomycin-resistant organisms is causing a serious public health problem, making it extremely difficult to treat infections, and also increasing the risk of patients acquiring infections while in a hospital. New compounds need to be developed in order to overcome this problem. Modification of the attached carbohydrates in the vancomycin molecule has proven to be key to overcoming the mechanisms of resistance in microbes. Yet, the number of available carbohydrate-modified vancomycin analogs is limited by the synthetic complexity of the parent glycopeptide natural product. Neoglycorandomization is a robust chemical method for 1 step sugar ligation which does not require any prior sugar protection or activation. This method is anticipated to provide a clear advantage in the discovery of new vancomycin-based therapeutics. In this work, we will synthesize 2 types of neoglycoside glycopeptide prototype molecules, 1 targeting VanA resistance, and the other, VanB resistance. These molecules will be subjected to screening for effectiveness. With the dramatic increase in the incidence of vancomycin-resistant bacterial infections, there is a critical need for new antibacterial therapeutics. Our work uses a unique technology to create novel derivatives of vancomycin by attaching sugars to the core molecule of the natural product, and will be specially designed to overcome resistant strains. [unreadable] [unreadable] [unreadable]